Aortic stenosis o may be used in children with no aortic valve

Clinical features of symptomatic disease calcification

o in adults limited to patients with critical
 chest pain aortic stenosis who are not fit for valve
 dyspnoea replacement
 syncope / presyncope (e.g. exertional dizziness)  Myocardial infarction: complications
 murmur  Patients are at risk of a number of immediate, early
o an ejection systolic murmur (ESM) is and late complications following a myocardial
classically seen in aortic stenosis infarction (MI).
o classically radiates to the carotids
o this is decreased following the Valsalva
manoeuvre  Cardiac arrest
This most commonly occurs due to patients
Features of severe aortic stenosis developing ventricular fibrillation and is the most
common cause of death following a MI. Patients are
 narrow pulse pressure managed as per the ALS protocol with defibrillation.
 slow rising pulse
 delayed ESM
 soft/absent S2  Cardiogenic shock

 S4 If a large part of the ventricular myocardium is

 thrill damaged in the infarction the ejection fraction of
 duration of murmur the heart may decrease to the point that the patient
 left ventricular hypertrophy or failure develops cardiogenic shock. This is difficult to treat.
Other causes of cardiogenic shock include the
'mechanical' complications such as left ventricular
Causes of aortic stenosis
free wall rupture as listed below. Patients may
require inotropic support and/or an intra-aortic
 degenerative calcification (most common cause in
balloon pump.
older patients > 65 years)
 bicuspid aortic valve (most common cause in
younger patients < 65 years)
 Chronic heart failure
 William's syndrome (supravalvular aortic stenosis)
 post-rheumatic disease
As described above, if the patient survives the acute
 subvalvular: HOCM
phase their ventricular myocardium may be
dysfunctional resulting in chronic heart failure. Loop
diuretics such as furosemide will decrease fluid
Management
overload. Both ACE-inhibitors and beta-blockers
have been shown to improve the long-term
 if asymptomatic then observe the patient is a
prognosis of patients with chronic heart failure.
general rule
 if symptomatic then valve replacement
 if asymptomatic but valvular gradient > 40  Tachyarrhythmias
mmHg and with features such as left ventricular
systolic dysfunction then consider surgery Ventricular fibrillation, as mentioned above, is the
 options for aortic valve replacement (AVR) include: most common cause of death following a MI. Other
o surgical AVR is the treatment of choice for common arrhythmias including ventricular
young, low/medium operative risk patients. tachycardia.
Cardiovascular disease may coexist. For this
reason, an angiogram is often done prior to  Bradyarrhythmias
surgery so that the procedures can be Atrioventricular block is more common
combined following inferior myocardial infarctions.
o transcatheter AVR (TAVR) is used for
patients with a high operative risk
 balloon valvuloplasty
 Pericarditis
Pericarditis in the first 48 hours following a
transmural MI is common (c. 10% of patients). The
pain is typical for pericarditis (worse on lying flat
etc), a pericardial rub may be heard and a
pericardial effusion may be demonstrated with an
echocardiogram.
Dressler's syndrome tends to occur around 2-6
weeks following a MI. The underlying
pathophysiology is thought to be an autoimmune
reaction against antigenic proteins formed as the
myocardium recovers. It is characterised by a
combination of fever, pleuritic pain, pericardial
effusion and a raised ESR. It is treated with NSAIDs.
 Left ventricular aneurysm
The ischaemic damage sustained may weaken the
myocardium resulting in aneurysm formation. This
is typically associated with persistent ST
elevation and left ventricular failure. Thrombus may
form within the aneurysm increasing the risk of
stroke. Patients are therefore anticoagulated.
 Left ventricular free wall rupture
This is seen in around 3% of MIs and occurs around
1-2 weeks afterwards. Patients present with acute
heart failure secondary to cardiac tamponade
(raised JVP, pulsus paradoxus, diminished heart
sounds). Urgent pericardiocentesis and
thoracotomy are required.
 Ventricular septal defect
Rupture of the interventricular septum usually
occurs in the first week and is seen in around 1-2%
of patients. Features: acute heart failure associated
with a pan-systolic murmur. An echocardiogram is
diagnostic and will exclude acute mitral
regurgitation which presents in a similar fashion.
Urgent surgical correction is needed.
 Acute mitral regurgitation
More common with infero-posterior infarction and
may be due to ischaemia or rupture of the papillary
muscle. Acute hypotension and pulmonary
oedema may occur. An early-to-mid systolic
murmur is typically heard. Patients are treated with
vasodilator therapy but often require emergency
surgical repair.
 This patient's ECG shows ST elevation in V1-V3 with
QS waves and upright T waves.
 Left ventricle aneurysms predispose to both ventricular
arrhythmias and cardiac thromboembolisms, both of
which are high up the differential in this case
Dermatitis herpetiformis
Dermatitis herpetiformis is an autoimmune blistering skin
disorder associated with coeliac disease. It is caused by deposition
of IgA in the dermis.
Features
 itchy, vesicular skin lesions on the extensor surfaces (e.g.
elbows, knees, buttocks)
Addison's disease: investigations
In a patient with suspected Addison's disease the definite
investigation is an ACTH stimulation test (short Synacthen test).
Plasma cortisol is measured before and 30 minutes after giving
Synacthen 250ug IM. Adrenal autoantibodies such as anti-21-
hydroxylase may also be demonstrated.
If an ACTH stimulation test is not readily available (e.g. in
primary care) then sending a 9 am serum cortisol can be useful:
 > 500 nmol/l makes Addison's very unlikely
 < 100 nmol/l is definitely abnormal
 100-500 nmol/l should prompt a ACTH stimulation test
to be performed
Associated electrolyte abnormalities are seen in around one-third
of undiagnosed patients:
 hyperkalaemia
 hyponatraemia
 hypoglycaemia
 metabolic acidosis
secondary adrenal failure, secondary being a failure of the
pituitary to make sufficient ACTH. For this, the long Synacthen
test should be used - a higher dose is given and then cortisol levels
measured over a longer time period.
Hypercalcaemia (6%) may also occur. This is partly due to a
reduction in calcium removal by the kidney and an increase in
mobilization of calcium from bone stores. Thyroid stimulating
hormone (TSH) can be elevated in primary hypoadrenalism due to
a loss of feedback on the pituitary gland.
If the cortisol post ACTH rises to > 420 nmol/L at 30 minutes, the
adrenal response to ACTH is adequate and Addison’s disease
(adrenal failure) can be excluded.
Cushing's syndrome: investigations
This section will consider:
 the general lab findings consistent with Cushing's syndrome
 tests to confirm whether a patient indeed has Cushing's
syndrome
 tests to find the underlying cause of Cushing's syndrome
It is useful to bear in mind the possible causes:
 iatrogenic: corticosteroid therapy
 ACTH-dependent causes
o Cushing's disease (a pituitary adenoma → ACTH
secretion)
o ectopic ACTH secretion secondary to a malignancy
 ACTH-independent causes
o adrenal adenoma
General findings consistent with Cushing's syndrome
A hypokalaemic metabolic alkalosis may be seen, along with
impaired glucose tolerance.
Ectopic ACTH secretion (e.g. secondary to small cell lung
cancer) is characteristically associated with very low
potassium levels.
Alcoholic liver disease
Alcoholic liver disease covers a spectrum of conditions:
 alcoholic fatty liver disease
 alcoholic hepatitis
 cirrhosis
Selected investigation findings:
 gamma-GT is characteristically elevated
 the ratio of AST:ALT is normally > 2, a ratio of > 3 is
strongly suggestive of acute alcoholic hepatitis
Selected management notes for alcoholic hepatitis:
 glucocorticoids (e.g. prednisolone) are often used during
acute episodes of alcoholic hepatitis
o Maddrey's discriminant function (DF) is often
used during acute episodes to determine who
would benefit from glucocorticoid therapy
o it is calculated by a formula using prothrombin
time and bilirubin concentration
 pentoxyphylline is also sometimes used
o the STOPAH study (see reference) compared
the two common treatments for alcoholic
hepatitis, pentoxyphylline and prednisolone. It
showed that prednisolone improved survival at
28 days and that pentoxyphylline did not
improve outcomes
Prednisolone 40mg for 28 days has been shown to increase
survival in patients with severe alcoholic hepatitis.
Combination therapy with prednisolone and pentoxifylline
confers no additional benefit over treatment with prednisolone
alone, whilst the use of N-acetylcysteine as monotherapy in
alcoholic hepatitis is not recommended.
Barrett's oesophagus
Barrett's refers to the metaplasia of the lower oesophageal
mucosa, with the usual squamous epithelium being replaced by
columnar epithelium. There is an increased risk of oesophageal
adenocarcinoma, estimated at 50-100 fold. There are no screening
programs for Barrett's - it's typically identified when patients have
an endoscopy for evaluation of upper gastrointestinal symptoms
such as dyspepsia.
Barrett's can be subdivided into short (<3cm) and long (>3cm).
The length of the affected segment correlates strongly with the
chances of identifying metaplasia. The overall prevalence of
Barrett's oesophagus is difficult to determine but may be in the
region of 1 in 20 and is identified in up to 12% of those
undergoing endoscopy for reflux.
Histological features
 the columnar epithelium may resemble that of either the
cardiac region of the stomach or that of the small
intestine (e.g. with goblet cells, brush border)
Risk factors
 gastro-oesophageal reflux disease (GORD) is the single
strongest risk factor
 male gender (7:1 ratio)
 smoking
 central obesity
Interestingly alcohol does not seem to be an independent risk
factor for Barrett's although it is associated with both GORD and
oesophageal cancer.
Whilst Barrett's oesophagus itself is asymptomatic clearly patients Cortisol ACTH Interpretation
will often have coexistent GORD symptoms.
Not Cushing's syndrome due to other causes (e.g.
Suppressed
Management suppressed adrenal adenomas)

Cushing's disease (i.e. pituitary adenoma →

 high-dose proton pump inhibitor Suppressed Suppressed
ACTH secretion)
o whilst this is commonly used in patients with
Barrett's the evidence base that this reduces the Not Not
change of progression to dysplasia or induces Ectopic ACTH syndrome
suppressed suppressed
regression of the lesion is limited
 endoscopic surveillance with biopsies Other tests
o for patients with metaplasia (but not dysplasia)
endoscopy is recommended every 3-5 years CRH stimulation
 if dysplasia of any grade is identified endoscopic
intervention is offered. Options include:  if pituitary source then cortisol rises
o radiofrequency ablation: preferred first-line  if ectopic/adrenal then no change in cortisol
treatment, particularly for low-grade dysplasia
o endoscopic mucosal resection Petrosal sinus sampling of ACTH may be needed to differentiate between
pituitary and ectopic ACTH secretion.

An insulin stress test is used to differentiate between true Cushing's and

pseudo-Cushing's.

Tests to confirm Cushing's syndrome

The two most commonly used tests are:

 overnight dexamethasone suppression test

o this is the most sensitive test and is now used first-
line to test for Cushing's syndrome
o patients with Cushing's syndrome do not have their
morning cortisol spike suppressed
 24 hr urinary free cortisol

Localisation tests

The first-line localisation is 9am and midnight plasma ACTH (and

cortisol) levels. If ACTH is suppressed then a non-ACTH dependent
cause is likely such as an adrenal adenoma

High-dose dexamethasone suppression test

The high-dose dexamethasone suppression test may be used to localise

the pathology resulting in Cushing's syndrome. This test may be
interpreted as follows:
 o prior stroke or transient ischaemic attack
o age 75 years or older
o hypertension
o diabetes mellitus
o heart failure
 prevention of VTE following hip/knee surgery
 treatment of DVT and PE

The table below summaries some of the differences between the

DOACs:

Dabigatran Rivaroxaban Apixaban Edoxaban

Direct Direct
Mechanism Direct factor Direct factor Xa
thrombin factor Xa
of action Xa inhibitor inhibitor
inhibitor inhibitor
Majority
Excretion Majority renal Majority liver Majority faecal
faecal
No authorised
reversal agent,
Andexanet Andexanet
Reversal Idarucizumab although
alfa* alfa*
andexanet alfa
has been studied

*Andexanet alfa is a recombinant form of human factor Xa

protein

Myeloma: features and investigation

Multiple myeloma (MM) is a haematological malignancy
characterised by plasma cell proliferation. It arises due to genetic
mutations which occur as B-lymphocytes differentiate into mature
plasma cells.

Features

Diagnosis The median age at presentation is 70 years old.

 skin biopsy: direct immunofluorescence shows Use the mnemonic CRABBI:

deposition of IgA in a granular pattern in the upper
dermis
Management
 gluten-free diet
 dapsone
Direct oral anticoagulants
Direct oral anticoagulants (DOACs) are currently used for the
following indications:
 prevention of stroke in non-valvular AF. NICE stipulate
that certain other risk factors should be present. These
are complicated and differ between the DOACs but
generally require one of the following to be present:
 Calcium
o hypercalcaemia
o primary factor: due primarily to increased
osteoclastic bone resorption caused by local
cytokines (e.g. IL-1, tumour necrosis factor)
released by the myeloma cells
o much less common contributing factors:
impaired renal function, increased renal tubular
calcium reabsorption and elevated PTH-rP
levels
o this leads to constipation, nausea, anorexia and
confusion
 Renal
o monoclonal production of immunoglobulins
results in light chain deposition within the renal
tubules
o this causes renal damage which presents as
dehydration and increasing thirst
 o other causes of renal impairment in myeloma
include amyloidosis, nephrocalcinosis,
nephrolithiasis
 Anaemia
o bone marrow crowding suppresses
erythropoiesis leading to anaemia
o this causes fatigue and pallor
 Bleeding
o bone marrow crowding also results in
thrombocytopenia which puts patients at
increased risk of bleeding and bruising
 Bones
o bone marrow infiltration by plasma cells and
cytokine-mediated osteoclast overactivity
creates lytic bone lesions
o this may present as pain (especially in the back)
and increases the risk of pathological fractures
 Infection
o a reduction in the production of normal
immunoglobulins results in increased
susceptibility to infection
Other features include
 historically a skeletal survey has been done to look for
bone lesions
 however, whole-body MRI is increasingly used and is
now recommended in the 2016 NICE guidelines
 X-rays: 'rain-drop skull' (likened to the pattern rain forms
after hitting a surface and splashing, where it leaves a
random pattern of dark spots). Note that a very similar,
but subtly different finding is found in primary
hyperparathyroidism - 'pepperpot skull'
Diagnostic criteria
The diagnostic criteria for multiple myeloma requires one major
and one minor criteria or three minor criteria in an individual who
has signs or symptoms of multiple myeloma.
Major criteria
 Plasmacytoma (as demonstrated on evaluation of biopsy
specimen)
 30% plasma cells in a bone marrow sample
 Elevated levels of M protein in the blood or urine

 amyloidosis e.g. macroglossia Minor criteria

 carpal tunnel syndrome
 neuropathy
 hyperviscosity  10% to 30% plasma cells in a bone marrow sample.
 Minor elevations in the level of M protein in the blood or
Investigations urine.
 Osteolytic lesions (as demonstrated on imaging studies).
Bloods  Low levels of antibodies (not produced by the cancer
cells) in the blood.

 full blood count: anaemia Typhus

 peripheral blood film: rouleaux formation Typhus is a group of rickettsial diseases transmitted between hosts
 urea and electrolytes: renal failure by arthropods. Examples include
 bone profile: hypercalcaemia

 endemic typhus
Protein electrophoresis o caused by Rickettsia typhi
o reservoir/vector: fleas on rats
o occurs throughout the world, typically in warm
 raised concentrations of monoclonal IgA/IgG proteins costal regions
will be present in the serum o relative bradycardia
 in the urine, they are known as Bence Jones proteins  epidemic typhus
o caused by Rickettsia prowazekii
o reservoir/vector: body louse
Bone marrow aspiration o more common in central and eastern Africa,
central and South America
 scrub typhus
o caused by Orientia tsutsugamushi
 confirms the diagnosis if the number of plasma cells is o reservoir/vector: harvest mites on humans or
significantly raised rodents
o more common in Asia
Imaging o black eschar at site of original inoculation
o relative bradycardia despite fever
  spotted fever  MERRF syndrome: myoclonus epilepsy with ragged-red
o caused by Rickettsia spotted fever group fibres
o spread by ticks  Kearns-Sayre syndrome: onset in patients < 20 years old,
o examples include Rocky Mountain spotted fever external ophthalmoplegia, retinitis pigmentosa. Ptosis
may be seen
 sensorineural hearing loss
Common features
Neuromyelitis optica
Neuromyelitis optica (NMO) is a monophasic or relapsing-
remitting demyelinating CNS disorder Although previously
 fever, headache, malaise
thought to be a variant of multiple sclerosis, it is now recognised
 rash to be a distinct disease, particularly prevalent in Asian
o typically maculopapular populations. It typically involves the optic nerves and cervical
o begins on the trunk and spreads to the spine, with imaging of the brain frequently normal. Vomiting is
extremities also a common presenting complaint.
 later complications
o meningoencephalitis Diagnosis requires bilateral optic neuritis, myelitis and 2 of the
following 3 criteria:

Management
 1. Spinal cord lesion involving 3 or more spinal levels
 2. Initially normal MRI brain
 doxycycline  3. Aquaporin 4 positive serum antibody

Mitochondrial diseases
Whilst most DNA is found in the cell nucleus, a small amount of
double-stranded DNA is present in the mitochondria. It encodes
protein components of the respiratory chain and some special
types of RNA
Mitochondrial inheritance has the following characteristics:
 inheritance is only via the maternal line as the sperm
contributes no cytoplasm to the zygote
 none of the children of an affected male will inherit the
disease
 all of the children of an affected female will inherit the
disease
 generally, encode rare neurological diseases
 poor genotype:phenotype correlation - within a tissue or
cell there can be different mitochondrial populations -
this is known as heteroplasmy
Histology
 muscle biopsy classically shows 'red, ragged fibres' due
to increased number of mitochondria
Examples include:
 Leber's optic atrophy
 MELAS syndrome: mitochondrial encephalomyopathy
lactic acidosis and stroke-like episodes
Management
 immunosuppressant e.g. with anti-CD20 agent
rituximab)
Stroke: management
The Royal College of Physicians (RCP) published guidelines on
the diagnosis and management of patients following a stroke in
2004. NICE updated their stroke guidelines in 2019.
Selected points relating to the management of acute stroke
include:
 blood glucose, hydration, oxygen saturation and
temperature should be maintained within normal limits
 blood pressure should not be lowered in the acute phase
unless there are complications e.g. Hypertensive
encephalopathy*
 aspirin 300mg orally or rectally should be given as soon
as possible if a haemorrhagic stroke has been excluded
 with regards to atrial fibrillation, the RCP state:
'anticoagulants should not be started until brain imaging
has excluded haemorrhage, and usually not until 14 days
have passed from the onset of an ischaemic stroke'
 if the cholesterol is > 3.5 mmol/l patients should be
commenced on a statin. Many physicians will delay
treatment until after at least 48 hours due to the risk of
haemorrhagic transformation
Thrombolysis for acute ischaemic stroke  confirmed occlusion of the proximal anterior
circulation demonstrated by computed tomographic
angiography (CTA) or magnetic resonance angiography
Thrombolysis with alteplase should only be given if: (MRA)

 it is administered within 4.5 hours of onset of stroke Offer thrombectomy as soon as possible to people who were last
symptoms (unless as part of a clinical trial) known to be well between 6 hours and 24 hours previously
 haemorrhage has been definitively excluded (i.e. (including wake-up strokes):
Imaging has been performed)

 confirmed occlusion of the proximal anterior

Contraindications to thrombolysis:
Absolute
- Previous intracranial
haemorrhage
- Seizure at onset of stroke
- Intracranial neoplasm
- Suspected subarachnoid
haemorrhage
- Stroke or traumatic brain injury
in preceding 3 months
- Lumbar puncture in preceding 7
days
- Gastrointestinal haemorrhage in
preceding 3 weeks
- Active bleeding
- Pregnancy
- Oesophageal varices
- Uncontrolled hypertension
>200/120mmHg
Relative
- Concurrent anticoagulation
(INR >1.7)
- Haemorrhagic diathesis
- Active diabetic
haemorrhagic retinopathy
- Suspected intracardiac
thrombus
- Major surgery / trauma in
the preceding 2 weeks
circulation demonstrated by CTA or MRA and
 if there is the potential to salvage brain tissue, as shown
by imaging such as CT perfusion or diffusion-weighted
MRI sequences showing limited infarct core volume
Consider thrombectomy together with intravenous thrombolysis
(if within 4.5 hours) as soon as possible for people last known to
be well up to 24 hours previously (including wake-up strokes):
 who have acute ischaemic stroke and confirmed
occlusion of the proximal posterior circulation (that is,
basilar or posterior cerebral artery) demonstrated by
CTA or MRA and
 if there is the potential to salvage brain tissue, as shown
by imaging such as CT perfusion or diffusion-weighted
MRI sequences showing limited infarct core volume
secondary prevention

NICE also published a technology appraisal in 2010 on the use of

Thrombectomy for acute ischaemic stroke
clopidogrel and dipyridamole

Recommendations from NICE include:

Mechanical thrombectomy is an exciting new treatment option for
patients with an acute ischaemic stroke. NICE incorporated
recommendations into their 2019 guidelines. It is important to
remember the significant resources and senior personnel to
provide such a service 24 hours a day. NICE recommend that all
decisions about thrombectomy take into account a patient's overall
clinical status:
 NICE recommend a pre-stroke functional status of less
than 3 on the modified Rankin scale and a score of more
than 5 on the National Institutes of Health Stroke Scale
(NIHSS)
 clopidogrel is now recommended by NICE ahead of
combination use of aspirin plus modified-release (MR)
dipyridamole in people who have had an ischaemic
stroke
 aspirin plus MR dipyridamole is now recommended after
an ischaemic stroke only if clopidogrel is contraindicated
or not tolerated, but treatment is no longer limited to 2
years' duration
 MR dipyridamole alone is recommended after an
ischaemic stroke only if aspirin or clopidogrel are
contraindicated or not tolerated, again with no limit on
duration of treatment

Offer thrombectomy as soon as possible and within 6 hours of

symptom onset, together with intravenous thrombolysis (if within With regards to carotid artery endarterectomy:
4.5 hours), to people who have:
acute ischaemic stroke and

 recommend if patient has suffered stroke or TIA in

the carotid territory and are not severely disabled
  should only be considered if carotid stenosis > 70%
according ECST** criteria or > 50% according to
NASCET*** criteria
*the 2009 Controlling hypertension and hypotension immediately
post-stroke (CHHIPS) trial may change thinking on this but
guidelines have yet to change to reflect this
**European Carotid Surgery Trialists' Collaborative Group
***North American Symptomatic Carotid Endarterectomy Trial
Seizure at onset of stroke
anticoagulation is not a treatment for acute stroke and is usually
delayed for two weeks after the initial event..
n. NICE advises that patients admitted within three days of an
acute stroke should have intermittent pneumatic compression
considered. This should be provided for 30 days or until the
patient is mobile or discharged.
Trigeminal autonomic cephalalgias
Trigeminal autonomic cephalalgias (TACs)
 cluster headache
 paroxysmal hemicrania
 hemicrania continua
 short-lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing (SUNCT
syndrome)
 short-lasting unilateral neuralgiform headache attacks
with cranial autonomic symptoms (SUNA)
Atypical trigeminal neuralgia is the diagnosis made when an
individual suffers from persistent lower intensity pain between
exacerbations, in contrast to the complete resolution of pain seen
in trigeminal neuralgia
Acute kidney injury: NICE guidelines and staging
This guideline discuss what increases the risk of AKI:
 Emergency surgery, ie, risk of sepsis or hypovolaemia
 Intraperitoneal surgery
 CKD, ie if eGFR < 60
 Diabetes
 Heart failure
 Age >65 years
 Liver disease
 Use of nephrotoxic drugs
o NSAIDs
o aminoglycosides
o ACE inhibitors/angiotensin II receptor
antagonists
o diuretics
Diagnostic criteria
It also defines the criteria for diagnosing AKI
 Rise in creatinine of 26µmol/L or more in 48 hours OR
 >= 50% rise in creatinine over 7 days OR
 Fall in urine output to < 0.5ml/kg/hour for more than 6
hours in adults (8 hours in children) OR
 >= 25% fall in eGFR in children / young adults in 7
days.
Staging criteria
The Kidney Disease: Improving Global Outcomes (KDIGO)
criteria are widely used to stage the AKI:
Increase in creatinine to 1.5-1.9 times baseline, or
Stage 1 Increase in creatinine by ≥26.5 µmol/L, or
Reduction in urine output to <0.5 mL/kg/hour for ≥ 6 hours
Increase in creatinine to 2.0 to 2.9 times baseline, or
Stage 2
Reduction in urine output to <0.5 mL/kg/hour for ≥12 hours
Increase in creatinine to ≥ 3.0 times baseline, or
Increase in creatinine to ≥353.6 µmol/L or
Stage 3 Reduction in urine output to <0.3 mL/kg/hour for ≥24 hours, or
The initiation of kidney replacement therapy, or,
In patients <18 years, decrease in eGFR to <35 mL/min/1.73 m2
Referral criteria
Refer to a nephrologist if any of the following apply:
 Renal tranplant
 ITU patient with unknown cause of AKI
 Vasculitis/ glomerulonephritis/ tubulointerstitial
nephritis/ myeloma
 AKI with no known cause
 Inadequate response to treatment
 Complications of AKI
 Stage 3 AKI (see guideline for details)
 CKD stage 4 or 5
 Qualify for renal replacement hyperkalaemia / metabolic
acidosis/ complications of uraemia/ fluid overload
(pulmonary oedema)
Membranous glomerulonephritis
Membranous glomerulonephritis is the commonest type of
glomerulonephritis in adults and is the third most common cause
of end-stage renal failure (ESRF). It usually presents with
nephrotic syndrome or proteinuria.
Renal biopsy demonstrates:

 electron microscopy: the basement membrane is

thickened with subepithelial electron dense deposits.
This creates a 'spike and dome' appearance

Causes

 idiopathic: due to anti-phospholipase A2 antibodies

 infections: hepatitis B, malaria, syphilis
 malignancy (in 5-20%): prostate, lung, lymphoma,
leukaemia
 drugs: gold, penicillamine, NSAIDs
 autoimmune diseases: systemic lupus erythematosus
(class V disease), thyroiditis, rheumatoid

Renal replacement therapy

Management
 all patients should receive an ACE inhibitor or an
angiotensin II receptor blocker (ARB):
o these have been shown to reduce proteinuria
and improve prognosis
 immunosuppression
o as many patients spontaneously improve only
patient with severe or progressive disease
require immunosuppression
o corticosteroids alone have not been shown to be
effective. A combination of corticosteroid +
another agent such as cyclophosphamide is
often used
 consider anticoagulation for high-risk patients
Prognosis - rule of thirds
Chronic kidney disease (CKD) is a relatively common condition,
affecting 1 in 8 people in the UK. Around 10% of those with
CKD will go on to develop renal failure, which is defined as a
glomerular filtration rate of less than 15ml/min. For patients with
renal failure, the management options are renal replacement
therapy (RRT), to take over the physiology of the kidneys, or
conservative management, which will be palliative.
There are several types of renal replacement therapy available to
patients:
 haemodialysis
 peritoneal dialysis
 renal transplant
The decision about which RRT option to pick should be made
jointly by the patient and their healthcare team, taking into
account the following:

 predicted quality of life

 one-third: spontaneous remission
 predicted life expectancy
 one-third: remain proteinuric
 patient preference
 one-third: develop ESRF
 co-existing medical conditions

Good prognostic features include female sex, young age at

Haemodialysis is the most common form of renal replacement
presentation and asymptomatic proteinuria of a modest degree at
therapy. This involves regular filtration of the blood through a
the time of presentation.
dialysis machine in hospital. Most patients need dialysis 3 times
per week, with each session lasting 3-5 hours. At least 8 weeks
before the commencement of treatment, the patient must undergo
surgery to create an arteriovenous fistula, which provides the site
for haemodialysis. Most commonly this is created in the lower
arm. Some patients may be trained to perform home
haemodialysis so that they do not have to regularly attend
hospital.

Peritoneal dialysis is another form of renal replacement therapy

where the filtration occurs within the patient's abdomen. Dialysis
solution is injected into the abdominal cavity through a permanent
catheter. The high dextrose concentration of the solution draws  insomnia
waste products from the blood into the abdominal cavity across  pruritus
the peritoneum. After several hours of dwell time, the dialysis  poor appetite
solution is then drained, removing the waste products from the  swelling
body, and exchanged for new dialysis solution. There are two  weakness
types of peritoneal dialysis:  weight gain/loss
 abdominal cramps
 nausea
 Continuous ambulatory peritoneal dialysis (CAPD) - as  muscle cramps
described above, with each exchange lasting 30-40  headaches
minutes and each dwell time lasting 4-8 hours. The  cognitive impairment
patient may go about their normal activities with the  anxiety
dialysis solution inside their abdomen  depression
 Automated peritoneal dialysis (APD) - a dialysis  sexual dysfunction
machine fills and drains the abdomen while the patient is
sleeping, performing 3-5 exchanges over 8-10 hours each
COPD: long-term oxygen therapy
night
The 2018 NICE guidelines on COPD clearly define which
patients should be assessed for and offered long-term oxygen
Renal transplantation involves the receipt of a kidney from therapy (LTOT). Patients who receive LTOT should breathe
either a live or deceased donor. The average wait for a kidney in supplementary oxygen for at least 15 hours a day. Oxygen
the UK is 3 years, though patients may also receive kidneys concentrators are used to provide a fixed supply for LTOT.
donated by cross-matched friends or family. The donor kidney is
transplanted into the groin, with the renal vessels connected to the Assess patients if any of the following:
external iliac vessels. The failing kidneys are not removed.
Following transplantation, the patient must take life-long
immunosuppressants to prevent rejection of the new kidney. The
average lifespan of a donor kidney is 10-12 years from deceased  very severe airflow obstruction (FEV1 < 30% predicted).
donors and 12-15 years from living donors. Assessment should be 'considered' for patients with
severe airflow obstruction (FEV1 30-49% predicted)
Complications of renal replacement therapy  cyanosis
 polycythaemia
Peritoneal  peripheral oedema
Haemodialysis Renal transplantation  raised jugular venous pressure
dialysis
Site infection Peritonitis DVT / PE  oxygen saturations less than or equal to 92% on room air
Sclerosing
Endocarditis Opportunistic infection Assessment is done by measuring arterial blood gases on 2
peritonitis
Malignancies occasions at least 3 weeks apart in patients with stable COPD on
Catheter optimal management.
Stenosis at site (particularly lymphoma
infection
and skin cancer)
Offer LTOT to patients with a pO2 of < 7.3 kPa or to those with
Catheter Bone marrow
Hypotension a pO2 of 7.3 - 8 kPa and one of the following:
blockage suppression
Recurrence of original
Cardiac arrhythmia Constipation  secondary polycythaemia
disease
 peripheral oedema
Air embolus Fluid retention Urinary tract obstruction
 pulmonary hypertension
Anaphylactic reaction
Hyperglycaemia Cardiovascular disease
to sterilising agents
Disequilibration
Hernias Graft rejection In terms of smoking, NICE advise the following:
syndrome
Back pain
 do not offer LTOT to people who continue to smoke
Malnutrition despite being offered smoking cessation advice and
treatment, and referral to specialist stop smoking
The average life expectancy of a patient with renal failure that services.
does not receive renal replacement therapy is 6 months. The
symptoms of renal failure that is not being adequately managed
with RRT are:
NICE suggest that a structured risk assessment is carried out
before offering LTOT, including:

 breathlessness
 fatigue
  the risks of falls from tripping over the equipment
 the risks of burns and fires, and the increased risk of
these for people who live in homes where someone
smokes (including e-cigarettes)
Osteoporosis: management
NICE guidelines were updated in 2008 on the secondary
prevention of osteoporotic fractures in postmenopausal women.
Key points include
 treatment is indicated following osteoporotic fragility
fractures in postmenopausal women who are confirmed
to have osteoporosis (a T-score of - 2.5 SD or below).
In women aged 75 years or older, a DEXA scan may not
be required 'if the responsible clinician considers it to be
clinically inappropriate or unfeasible'
 vitamin D and calcium supplementation should be
offered to all women unless the clinician is confident
they have adequate calcium intake and are vitamin D
replete
 alendronate is first-line
 around 25% of patients cannot tolerate alendronate,
usually due to upper gastrointestinal problems. These
patients should be offered risedronate or etidronate (see
treatment criteria below)
 strontium ranelate and raloxifene are recommended if
patients cannot tolerate bisphosphonates (see treatment
criteria below)
Treatment criteria for patients not taking alendronate
Unfortunately, a number of complicated treatment cut-off tables
have been produced in the latest guidelines for patients who do
not tolerate alendronate
These take into account a patients age, their T-score and the
number of risk factors they have from the following list:
 parental history of hip fracture
 alcohol intake of 4 or more units per day
 rheumatoid arthritis
It is very unlikely that examiners would expect you to have
memorised these risk tables so we've not included them in the
revision notes but they may be found by following the NICE link.
The most important thing to remember is:
 the T-score criteria for risedronate or etidronate are less
than the others implying that these are the second line
drugs
 if alendronate, risedronate or etidronate cannot be taken
then strontium ranelate or raloxifene may be given based
on quite strict T-scores (e.g. a 60-year-old woman would
need a T-score < -3.5)
 the strictest criteria are for denosumab
Supplementary notes on treatment
Bisphosphonates
 alendronate, risedronate and etidronate are all licensed
for the prevention and treatment of post-menopausal and
glucocorticoid-induced osteoporosis
 all three have been shown to reduce the risk of both
vertebral and non-vertebral fractures although
alendronate, risedronate may be superior to etidronate in
preventing hip fractures
 ibandronate is a once-monthly oral bisphosphonate
Vitamin D and calcium
 poor evidence base to suggest reduced fracture rates in
the general population at risk of osteoporotic fractures -
may reduce rates in frail, housebound patients
Raloxifene - selective oestrogen receptor modulator (SERM)
 has been shown to prevent bone loss and to reduce the
risk of vertebral fractures, but has not yet been shown to
reduce the risk of non-vertebral fractures
 has been shown to increase bone density in the spine and
proximal femur
 may worsen menopausal symptoms
 increased risk of thromboembolic events
 may decrease risk of breast cancer
Strontium ranelate
 'dual action bone agent' - increases deposition of new
bone by osteoblasts (promotes differentiation of pre-
osteoblast to osteoblast) and reduces the resorption of
bone by inhibiting osteoclasts
 concerns regarding the safety profile of strontium have
been raised recently. It should only be prescribed by a
specialist in secondary care
 due to these concerns the European Medicines Agency in
2014 said it should only be used by people for whom
there are no other treatments for osteoporosis
 increased risk of cardiovascular events: any history of
cardiovascular disease or significant risk of
cardiovascular disease is a contraindication
 increased risk of thromboembolic events: a Drug Safety
Update in 2012 recommended it is not used in patients
with a history of venous thromboembolism
 may cause serious skin reactions such as Stevens
Johnson syndrome
Denosumab
  human monoclonal antibody that inhibits RANK ligand,
which in turn inhibits the maturation of osteoclasts
 given as a single subcutaneous injection every 6 months
 initial trial data suggests that it is effective and well
tolerated
Teriparatide
 recombinant form of parathyroid hormone
 very effective at increasing bone mineral density but role from activated charcoal to reduce absorption of the drug.
in the management of osteoporosis yet to be clearly
defined
Hormone replacement therapy
 has been shown to reduce the incidence of vertebral
fracture and non-vertebral fractures
 due to concerns about increased rates of cardiovascular
disease and breast cancer it is no longer recommended
for primary or secondary prevention of osteoporosis
unless the woman is suffering from vasomotor symptoms
Hip protectors
 evidence to suggest significantly reduce hip fractures in
nursing home patients
 compliance is a problem
Falls risk assessment
 no evidence to suggest reduced fracture rates
 however, do reduce rate of falls and should be
considered in management of high risk patients
MRI showing osteoporotic fractures of the 8th and 10th thoracic vertebrae.
Paracetamol overdose: management
The following is based on 2012 Commission on Human
Medicines (CHM) review of paracetamol overdose management.
The big change in these guidelines was the removal of the 'high-
risk' treatment line on the normogram. All patients are therefore
treated the same regardless of risk factors for hepatotoxicity. The
National Poisons Information Service/TOXBASE should always
be consulted for situations outside of the normal parameters.
The minority of patients who present within 1 hour may benefit
Acetylcysteine should be given if:
 the plasma paracetamol concentration is on or above a
single treatment line joining points of 100 mg/L at 4
hours and 15 mg/L at 15 hours, regardless of risk factors
of hepatotoxicity
 there is a staggered overdose* or there is doubt over the
time of paracetamol ingestion, regardless of the plasma
paracetamol concentration; or
 patients who present 8-24 hours after ingestion of an
acute overdose of more than 150 mg/kg of paracetamol
even if the plasma-paracetamol concentration is not yet
available
 patients who present > 24 hours if they are clearly
jaundiced or have hepatic tenderness, their ALT is above
the upper limit of normal
o acetylcysteine should be continued if the
paracetamol concentration or ALT remains
elevated whilst seeking specialist advice
Acetylcysteine is now infused over 1 hour (rather than the
previous 15 minutes) to reduce the number of adverse
effects. Acetylcysteine commonly causes an anaphylactoid
reaction (non-IgE mediated mast cell release). Anaphylactoid
reactions to IV acetylcysteine are generally treated by stopping
the infusion, then restarting at a slower rate.
 King's College Hospital criteria for liver transplantation (paracetamol liver
failure)
Arterial pH < 7.3, 24 hours after ingestion
or all of the following:
 prothrombin time > 100 seconds
 creatinine > 300 µmol/l
 grade III or IV encephalopathy
*an overdose is considered staggered if all the tablets were not
taken within 1 hour
Angina pectoris: drug management
The management of stable angina comprises lifestyle changes,
medication, percutaneous coronary intervention and surgery.
NICE produced guidelines in 2011 covering the management of
stable angina
Medication
 all patients should receive aspirin and a statin in the
absence of any contraindication
 sublingual glyceryl trinitrate to abort angina attacks
 NICE recommend using either a beta-blocker or a
calcium channel blocker first-line based on
'comorbidities, contraindications and the person's
preference'
 if a calcium channel blocker is used as monotherapy a
rate-limiting one such as verapamil or diltiazem should
be used
 if used in combination with a beta-blocker then use a
longer-acting dihydropyridine calcium channel blocker
(e.g. amlodipine, modified-release nifedipine)
o remember that beta-blockers should not be
prescribed concurrently with verapamil (risk of
complete heart block)
 if there is a poor response to initial treatment then
medication should be increased to the maximum
tolerated dose (e.g. for atenolol 100mg od)
 if a patient is still symptomatic after monotherapy with a
beta-blocker add a calcium channel blocker and vice
versa
 if a patient is on monotherapy and cannot tolerate the
addition of a calcium channel blocker or a beta-blocker
then consider one of the following drugs:
o a long-acting nitrate
o ivabradine
o nicorandil
o ranolazine
 if a patient is taking both a beta-blocker and a calcium-
channel blocker then only add a third drug whilst a
patient is awaiting assessment for PCI or CABG
Nitrate tolerance
 many patients who take nitrates develop tolerance and
experience reduced efficacy
 NICE advises that patients who take standard-release
isosorbide mononitrate should use an asymmetric dosing
interval to maintain a daily nitrate-free time of 10-14
hours to minimise the development of nitrate tolerance
 this effect is not seen in patients who take once-daily
modified-release isosorbide mononitrate
. Sick sinus syndrome would be a contraindication to ivabradine
and calcium channel blocker. In addition, alcohol excess and
recent decompensation, despite current abstinence, is likely to
have resulted in liver dysfunction, an absolute contraindication to
ranolazine.
Nicorandil is only contraindicated in LV failure and cardiogenic
shock, acting as a potassium channel opener, and is thus the only
appropriate anti-anginal in this scenario
Ranolazine acts a late inward calcium channel antagonist but is
contra-indicated in severe renal disease.
Isosorbide mononitrate would be appropriate to use as a third
agent, if the combination of a beta-blocker and CCB was not
adequate.Dosing at 0800 and 2200 would leave a 12 hour total
period between doses, but given the fact that the immediate
release form acts for up to 6 hours, tolerance is more likely to
develop.
Ivabradine is recommended by NICE in patients who experience
angina despite beta-blocker/calcium channel blocker
monotherapy, or have NYHA II-IV symptoms with an ejection
fraction <35% on optimal heart failure therapy. heart rates over
70bpm
Ivabradine is a hyperpolarisation-activated cyclic nucleotide-
gated (HCN) channel blocker that produces a negative
chronotropic effect in the sinoatrial (SA) node, reducing the heart
rate and therefore symptoms of angina.
Aortic regurgitation
Aortic regurgitation (AR) is the leaking of the aortic valve of the
heart that causes blood to flow in the reverse direction during
ventricular diastole.
It can be caused either by disease of the aortic valve or by
distortion or dilation of the aortic root and ascending aorta.
 Causes of AR due place. Women who are at high risk of developing pre-eclampsia
Causes of AR due to valve should take aspirin 75mg od from 12 weeks until the birth of the
to aortic root
disease baby.
disease
 rheumatic fever: Hypertension in pregnancy in usually defined as:
the most common  bicuspid aortic
cause in the valve (affects both
developing world  systolic > 140 mmHg or diastolic > 90 mmHg
the valves and the
 calcific valve  or an increase above booking readings of > 30 mmHg
aortic root)
disease systolic or > 15 mmHg diastolic

 connective tissue spondylarthropathi
Chronic After establishing that the patient is hypertensive they should be
diseases e.g. es (e.g. ankylosing
presentation categorised into one of the following groups
rheumatoid spondylitis)
arthritis/SLE  hypertension Pregnancy-induced
 bicuspid aortic  syphilis hypertension
valve (affects both  Marfan's, Pre-existing hypertension (PIH, also known as Pre-eclampsia
the valves and the Ehler-Danlos gestational
aortic root) syndrome hypertension)

 infective A history of hypertension

Acute endocarditis  aortic Hypertension (as
presentation dissection before pregnancy or an
defined above)
elevated blood pressure >
occurring in the
Features 140/90 mmHg before 20
second half of Pregnancy-
weeks gestation
pregnancy (i.e. after induced
 early diastolic murmur: intensity of the murmur is 20 weeks) hypertension in
No proteinuria, no oedema
increased by the handgrip manoeuvre association with
 collapsing pulse No proteinuria, no proteinuria (>
Occurs in 3-5% of
 wide pulse pressure oedema 0.3g / 24 hours)
pregnancies and is more
 Quincke's sign (nailbed pulsation) common in older women
 De Musset's sign (head bobbing) Occurs in around 5- Oedema may
 mid-diastolic Austin-Flint murmur in severe AR - due to 7% of pregnancies occur but is now
If a pregnant woman takes
partial closure of the anterior mitral valve cusps caused less commonly
an ACE inhibitor or
by the regurgitation streams Resolves following used as a criteria
angiotensin II receptor
birth (typically after
blocker (ARB) for pre-
one month). Women Occurs in
existing hypertension this
with PIH are at around 5% of
Suspected AR should be investigated with echocardiography. should be stopped
increased risk of pregnancies
immediately and alternative
future pre-eclampsia
Management antihypertensives started
or hypertension later
(e.g. labetalol) whilst
in life
 medical management of any associated heart failure awaiting specialist review
 surgery: aortic valve indications include
o symptomatic patients with severe AR
o asymptomatic patients with severe AR who Management
have LV systolic dysfunction

Hypertension in pregnancy  oral labetalol is now first-line following the 2010 NICE
It's useful to remember that in normal pregnancy: guidelines
 oral nifedipine (e.g. if asthmatic) and hydralazine

 blood pressure usually falls in the first trimester
(particularly the diastolic), and continues to fall until 20-
24 weeks
 after this time the blood pressure usually increases to
pre-pregnancy levels by term
Autoimmune haemolytic anaemia
Autoimmune haemolytic anaemia (AIHA) may be divided in to
'warm' and 'cold' types, according to at what temperature the
antibodies best cause haemolysis. It is most commonly idiopathic
but may be secondary to a lymphoproliferative disorder, infection
or drugs.

NICE published guidance in 2010 on the management of Investigations

hypertension in pregnancy. They also made recommendations on
reducing the risk of hypertensive disorders developing in the first
  general features of haemolytic anaemia Disorder Underlying defect Notes
o anaemia
o reticulocytosis catalase-positive
bacteria (e.g. Staphylococcus
o low haptoglobin ability of
aureus and fungi (e.g. Aspergillus)
o raised lactate dehydrogenase (LDH) and phagocytes to
disease Negative nitroblue-tetrazolium test
indirect bilirubin produce reactive
Abnormal dihydrorhodamine flow
o blood film: spherocytes and reticulocytes oxygen species
cytometry test
 specific features of autoimmune haemolytic anaemia
o positive direct antiglobulin test (Coombs' test).
Affected children have 'partial
Microtubule
albinism' and peripheral
Chediak- polymerization
neuropathy. Recurrent bacterial
Warm AIHA Higashi defect which leads
infections are seen
Warm is the most common type of AIHA. In warm AIHA the syndrome to a decrease in
Giant granules in neutrophils and
antibody (usually IgG) causes haemolysis best at body phagocytosis
platelets
temperature and haemolysis tends to occur in extravascular sites,
for example the spleen. Recurrent bacterial infections.
Defect of LFA-1
Leukocyte Delay in umbilical cord sloughing
integrin (CD18)
Causes of warm AIHA adhesion may be seen
protein on
deficiency Absence of neutrophils/pus at sites
neutrophils
 idiopathic of infection
 autoimmune disease: e.g. systemic lupus erythematosus*
 neoplasia B-cell disorders
o lymphoma Disorder Underlying defect Notes
o chronic lymphocytic leukaemia Low antibody levels, specifically
 drugs: e.g. methyldopa Common in immunoglobulin (Ig) types IgG,
variable IgM and IgA. Recurrent chest
Many varying causes
Management immunodef infections. May also predispose to
iciency autoimmune disorders and
 treatment of any underlying disorder lymphona
 steroids (+/- rituximab) are generally used first-line Bruton's Defect in Bruton's
X-linked recessive. Recurrent
(x-linked) tyrosine kinase (BTK)
bacterial infections are seen
Cold AIHA congenital gene that leads to a
Absence of B-cells with reduced
The antibody in cold AIHA is usually IgM and causes haemolysis agammaglo severe block in B cell
immunoglogulins of all classes
best at 4 deg C. Haemolysis is mediated by complement and is bulinaemia development
more commonly intravascular. Features may include symptoms of Most common primary antibody
Raynaud's and acrocynaosis. Patients respond less well to steroids deficiency. Recurrent sinus and
respiratory infections
Causes of cold AIHA
Selective
Associated with coeliac disease
 neoplasia: e.g. lymphoma immunoglo Maturation defect in B
and may cause false negative
 infections: e.g. mycoplasma, EBV bulin A cells
coeliac antibody screen
deficiency
Severe reactions to blood
*systemic lupus erythematosus can rarely be associated with a transfusions may occur (anti-IgA
mixed-type autoimmune haemolytic anaemia antibodies → analphylaxis)

SLE is an important risk factor for IgG-mediated, warm T-cell disorders

autoimmune haemolytic anaemia. This is associated with
extravascular haemolysis which can lead to a hypertrophic spleen.
Underlying
Primary immunodeficiency Disorder Notes
defect
Primary immunodeficiency disorders may be classified according
to which component of the immune system they affect. 22q11.2 Common features include
deletion, failure congenital heart disease
Neutrophil disorders DiGeorge to develop 3rd (e.g. tetralogy of Fallot), learning
syndrome and 4th difficulties, hypocalcaemia,
pharyngeal recurrent viral/fungal diseases, cleft
Disorder Underlying defect Notes pouches palate
Chronic Lack of NADPH Causes recurrent pneumonias and
granulomatous oxidase reduces abscesses, particularly due to Combined B- and T-cell disorders
Disorder Underlying defect Notes  Stage 1: symptoms similar to alcohol intoxication:
confusion, slurred speech, dizziness
Many varying causes. Most  Stage 2: metabolic acidosis with high anion gap and high
common (X-linked) due Recurrent infections due to osmolar gap. Also tachycardia, hypertension
Severe to defect in the common viruses, bacteria and fungi.
 Stage 3: acute kidney injury
combined gamma chain, a protein used Reduced T-cell receptor
immunod in the receptors for IL-2 and excision circles
eficiency other interleukins. Other Stem cell transplantation
causes include adenosine may be successful Management has changed in recent times
deaminase deficiency
Autosomal recessive.
Features include cerebellar  ethanol has been used for many years
ataxia, telangiectasia  works by competing with ethylene glycol for the enzyme
Ataxic alcohol dehydrogenase
Defect in DNA repair (spider angiomas),
telangiect  this limits the formation of toxic metabolites (e.g.
enzymes recurrent chest infections
asia glycoaldehyde and glycolic acid) which are responsible
and 10% risk of
developing malignancy, for the haemodynamic/metabolic features of poisoning
lymphoma or leukaemia  fomepizole, an inhibitor of alcohol dehydrogenase, is
now used first-line in preference to ethanol
X-linked recessive.
Features include recurrent  haemodialysis also has a role in refractory cases
bacterial
Wiskott- infections, eczema, thromb
Aldrich Defect in WASP gene ocytopaenia. Fomepizole is used in ethylene glycol poisoning by acting to
syndrome Low IgM levels prevent the breakdown of these toxins into their active toxic
Increased risk of metabolites.
autoimmune disorders and
malignancy
Hyper Eczema herpeticum
Infection/Pneumocystis pn Eczema herpeticum describes a severe primary infection of the
IgM
Mutations in the CD40 gene eumonia, hepatitis, skin by herpes simplex virus 1 or 2.
Syndrom
diarrhoea
es
It is more commonly seen in children with atopic eczema and
often presents as a rapidly progressing painful rash.
Hyper IgM syndrome is a heterogeneous group of disorders
characterised by defective class-switch recombination leading to
raised serum IgM with low levels of IgG and IgA. The most
common form is an X-linked recessive trait due to mutation of
CD40LG gene affecting roughly 2/1,000,000 males. The
mechanism involves impaired immune signalling between T and
B cells leading to primary immune deficiency.

Chediak-Higashi syndrome and chronic granulomatous

disease are disorders associated with neutrophil dysfunction
predisposing to recurrent bacterial infections. They are not
associated with hypogammaglobulinaemia

On examination, monomorphic punched-out erosions (circular,

Wiskott-Aldrich syndrome is incorrect. This is caused by a
defect in the WASP gene. This causes recurrent bacterial
infections but is also typically associated with eczema and
thrombocytopenia
Ethylene glycol toxicity
Ethylene glycol is a type of alcohol used as a coolant or antifreeze
Features of toxicity are divided into 3 stages:
depressed, ulcerated lesions) usually 1–3 mm in diameter are
typically seen.
As it is potentially life-threatening children should
be admitted for IV aciclovir.
Eczema herpeticum rash can be described as monomorphic
punched-out erosions (circular, depressed, ulcerated lesions)
usually 1–3 mm in diameter this is accompanied by pruritic
blisters.
Familial hypercholesterolaemia
Familial hypercholesterolaemia (FH) is an autosomal
dominant condition that is thought to affect around 1 in
500 people. It results in high levels of LDL-cholesterol which, if
untreated, may cause early cardiovascular disease (CVD). FH is
caused by mutations in the gene which encodes the LDL-receptor
protein.
Case finding:
 NICE suggest that we should suspect FH as a possible
diagnosis in adults with:
o a total cholesterol level greater than 7.5 mmol/l
and/or
o a personal or family history of premature
coronary heart disease (an event before 60 years
in an index individual or first-degree relative)
 children of affected parents:
o if one parent is affected by familial
hypercholesterolaemia, arrange testing in
children by age 10
o if both parents are affected by familial
hypercholesterolaemia, arrange testing in
children by age 5
Clinical diagnosis is now based on the Simon Broome criteria:
 in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C
> 4.9 mmol/l or children TC > 6.7 mmol/l and LDL-C >
4.0 mmol/l, plus:
 for definite FH: tendon xanthoma in patients or 1st or
2nd degree relatives or DNA-based evidence of FH
 for possible FH: family history of myocardial infarction
below age 50 years in 2nd degree relative, below age 60
in 1st degree relative, or a family history of raised
cholesterol levels
Management
 the use of CVD risk estimation using standard tables is
not appropriate in FH as they do not accurately reflect
the risk of CVD
 referral to a specialist lipid clinic is usually required
 high-dose statins are usually used first-line
 first-degree relatives have a 50% chance of having the
disorder and should therefore be offered screening. This
includes children who should be screened by the age of
10 years if there is one affected parent
 statins should be discontinued in women 3 months before
conception due to the risk of congenital defects
Evolocumab prevents PCSK9-mediated LDL receptor
degradation.
 NICE suggest that we should suspect FH as a possible
diagnosis in adults with:
o a total cholesterol level greater than 7.5 mmol/l
and/or
o a personal or family history of premature
coronary heart disease (an event before 60 years
in an index individual or first-degree relative)
 children of affected parents:
o if one parent is affected by familial
hypercholesterolaemia, arrange testing in
children by age 10
o if both parents are affected by familial
hypercholesterolaemia, arrange testing in
children by age 5
Statins should be discontinued in women 3 months before
conception due to the risk of congenital defects
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis (SBP) is a form of peritonitis
usually seen in patients with ascites secondary to liver cirrhosis.
Features
 ascites
 abdominal pain
 fever
Diagnosis
 paracentesis: neutrophil count > 250 cells/ul
 the most common organism found on ascitic fluid culture
is E. coli
Management
 intravenous cefotaxime is usually given
Antibiotic prophylaxis should be given to patients with ascites if:
 patients who have had an episode of SBP
 patients with fluid protein <15 g/l and either Child-Pugh
score of at least 9 or hepatorenal syndrome
 NICE recommend: 'Offer prophylactic oral ciprofloxacin
or norfloxacin for people with cirrhosis and ascites with
an ascitic protein of 15 g/litre or less until the ascites has
resolved'
Alcoholic liver disease is a marker of poor prognosis in SBP.
All patients with SBP should have repeat ascitic tap at 48 hours to
ensure neutrophil count of fluid is improving on antibiotics.
However, this has not been proven to reduce mortality.
Rifaximin is an antibiotic licensed for use in patients with
alcoholic cirrhosis with previous hepatic encephalopathy. It can
be used prophylactically to prevent ammonia-releasing bacteria in
the gut precipitating further episodes, However, it is notused in
SBP.
long-term prophylaxis with a quinolone such as ciprofloxacin or
norfloxacin has been shown to reduce the recurrence rate of SBP.
This is particularly important in patients who have a particularly Mechanism of Adverse
low ascitic fluid protein. Drug Indications
action effects/toxicity
r)
The most common causative organisms of SBP are gram-negative
enteric bacteria. E coli is by far the most common followed
by Klebsiella Anti-retroviral agent used in HIV

Nucleoside analogue reverse transcriptase inhibitors (NRTI)

Antiviral agents
Mechanism of Adverse  examples: zidovudine (AZT), didanosine, lamivudine,
Drug Indications
action effects/toxicity stavudine, zalcitabine
Guanosine analog,
phosphorylated by
Aciclo thymidine kinase Crystalline Protease inhibitors (PI)
HSV, VZV
vir which in turn nephropathy
inhibits the viral
DNA polymerase
 inhibits a protease needed to make the virus able to
Guanosine analog, survive outside the cell
phosphorylated by  examples: indinavir, nelfinavir, ritonavir, saquinavir
Gancic thymidine kinase Myelosuppression/
CMV
lovir which in turn agranulocytosis
inhibits the viral
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
DNA polymerase
Guanosine analog
which inhibits
 examples: nevirapine, efavirenz
inosine
monophosphate Chronic
Ribavi
(IMP) hepatitis C, Haemolytic anaemia
rin
dehydrogenase, RSV
interferes with the Whilst in most cases, oseltamivir (a neuraminidase inhibitor) is
capping of viral first line treatment for influenza, the BNF advises that for severely
mRNA immunocompromised individuals zanamivir should be first line
treatment.
Inhibits uncoating
(M2 protein) of Influenza,
Amant Confusion, ataxia,
virus in cell. Also Parkinson's
adine slurred speech STI: ulcers
releases dopamine disease
from nerve endings Genital herpes is most often caused by the herpes simplex virus
(HSV) type 2 (cold sores are usually due to HSV type 1). Primary
Oselta Inhibits attacks are often severe and associated with fever whilst
Influenza
mivir neuraminidase subsequent attacks are generally less severe and localised to one
Pyrophosphate CMV, HSV site. There is typically multiple painful ulcers.
Nephrotoxicity, hypo
Foscar analog which if not
calcaemia, hypomag Syphilis is a sexually transmitted infection caused by the
net inhibits viiral DNA responding
nasaemia, seizures spirochaete Treponema pallidum. Infection is characterised by
polymerase to aciclovir
primary, secondary and tertiary stages. A painless ulcer (chancre)
Chronic is seen in the primary stage. The incubation period= 9-90 days.
Human
hepatitis B Flu-like symptoms,
Interfe glycoproteins which
& C, hairy anorexia, Chancroid is a tropical disease caused by Haemophilus ducreyi. It
ron-α inhibit synthesis of
cell myelosuppression causes painful genital ulcers associated with unilateral, painful
mRNA
leukaemia inguinal lymph node enlargement. The ulcers typically have a
Cidofo Acyclic nucleoside CMV Nephrotoxicity sharply defined, ragged, undermined border.
vir phosphonate, and is retinitis in
therefore HIV Lymphogranuloma venereum (LGV) is caused by Chlamydia
independent of trachomatis. Typically infection comprises of three stages
phosphorylation by
viral enzymes
(compare and
 stage 1: small painless pustule which later forms an ulcer
contrast with
 stage 2: painful inguinal lymphadenopathy
aciclovir/ganciclovi
 stage 3: proctocolitis
  steroids
LGV is treated using doxycycline.  cyclophosphamide

Other causes of genital ulcers

One of the main complications is pulmonary haemorrhage.
 Behcet's disease Factors that increase the likelihood of this include:
 carcinoma
 granuloma inguinale: Klebsiella granulomatis*  smoking
 lower respiratory tract infection
 pulmonary oedema
*previously called Calymmatobacterium granulomatis  inhalation of hydrocarbons
 young males

Lymphogranuloma venereum Anti-GBM antibody is correct. The patient presents with

Groove sign is separation inguinal nodes by the inguinal ligament
and is characteristic of the disease.
Complications of the disease include: genital elephantiasis,
hepatitis, infertility, pelvic inflammatory disease, arthritis and fitz
hugh curtis syndrome.
haemoptysis and deranged renal function with multifocal airspace
opacification
Dehydration may decrease the likelihood of a pulmonary
haemorrhage. Pulmonary oedema is associated with an increased
risk

Chronic kidney disease: eGFR and classification

Serum creatinine may not provide an accurate estimate of renal
Anti-glomerular basement membrane (GBM) disease function due to differences in muscle. For this reason, formulas
(Goodpasture's syndrome) were developed to help estimate the glomerular filtration rate
Anti-glomerular basement membrane (GBM) disease (previously (estimated GFR or eGFR). The most commonly used formula is
known as Goodpasture's syndrome) is a rare type of small-vessel the Modification of Diet in Renal Disease (MDRD) equation,
vasculitis associated with both pulmonary haemorrhage and which uses the following variables:
rapidly progressive glomerulonephritis. It is caused by anti-
glomerular basement membrane (anti-GBM) antibodies against  serum creatinine
type IV collagen. Goodpasture's syndrome is more common in  age
men (sex ratio 2:1) and has a bimodal age distribution (peaks in
 gender
20-30 and 60-70 age bracket). It is associated with HLA DR2.
 ethnicity
Features
Factors which may affect the result

 pulmonary haemorrhage  pregnancy

 rapidly progressive glomerulonephritis  muscle mass (e.g. amputees, body-builders)
o this typically results in a rapid onset acute  eating red meat 12 hours prior to the sample being taken
kidney injury
o nephritis → proteinuria + haematuria CKD may be classified according to GFR:

CKD
GFR range
Investigations stage
Greater than 90 ml/min, with some sign of kidney damage
1 on other tests (if all the kidney tests* are normal, there is no
 renal biopsy: linear IgG deposits along the basement CKD)
membrane 60-90 ml/min with some sign of kidney damage (if kidney
 raised transfer factor secondary to pulmonary 2
tests* are normal, there is no CKD)
haemorrhages
3a 45-59 ml/min, a moderate reduction in kidney function
3b 30-44 ml/min, a moderate reduction in kidney function
Management 4 15-29 ml/min, a severe reduction in kidney function
Less than 15 ml/min, established kidney failure - dialysis or
5
a kidney transplant may be needed
 plasma exchange (plasmapheresis)

*i.e. normal U&Es and no proteinuria
Prostate cancer: management
Localised prostate cancer (T1/T2)
Treatment depends on life expectancy and patient choice. Options
include:
 conservative: active monitoring & watchful waiting
 radical prostatectomy
 radiotherapy: external beam and brachytherapy
Localised advanced prostate cancer (T3/T4)
Options include:
 hormonal therapy: see below
 radical prostatectomy: erectile dysfunction is a common
complication
 radiotherapy
o external beam and brachytherapy
o patients may develop proctitis and are also
at increased risk of bladder, colon, and rectal
cancer following radiotherapy for prostate
cancer
Metastatic prostate cancer disease - hormonal therapy
One of the key aims of treating advanced prostate cancer is
reducing androgen levels. A combination of approaches if often
used.
Anti-androgen therapy
 synthetic GnRH agonist or antagonists
o GnRH agonists: e.g. Goserelin (Zoladex)
o paradoxically result in lower LH levels longer
term by causing overstimulation, resulting in
disruption of endogenous hormonal feedback
systems. The testosterone level will therefore
rise initially for around 2-3 weeks before falling
to castration leves
o initially therapy is often covered with an anti-
androgen to prevent a rise in testosterone -
'tumour flare'. The resultant stimulation of
prostate cancer growth may result in bone pain,
bladder obstruction and other symptoms
 interestingly, GnRH antagonists such as degarelix are
being evaluated to suppress testosterone while avoiding
the flare phenomenon
 bicalutamide
o non-steroidal anti-androgen
o blocks the androgen receptor
 cyproterone acetate
o steroidal anti-androgen
o prevents DHT binding from intracytoplasmic
protein complexes
o used less commonly since introduction of non-
steroidal anti-androgens
 abiraterone
o androgen synthesis inhibitor
o option for the treatment of hormone-relapsed
metastatic prostate cancer in patients who have
no or mild symptoms after androgen deprivation
therapy has failed, and before chemotherapy is
indicated
 bilateral orchidectomy
o used to rapidly reduce testosterone levels
Chemotherapy with docetaxel
Abiraterone acetate is a selective androgen synthesis inhibitor that
works by blocking cytochrome P450 17 alpha-hydroxylase.
Bicalutamide is a commonly used non-steroidal, anti-androgen
therapy. It works by blocking the androgen receptors and is
typically used together with a gonadotropin-releasing hormone
(GnRH) analogue or orchidectomy in the management of
advanced prostate cancer.
Abiraterone is an example of an androgen synthesis blocker,
inhibiting enzymes needed for production
Goserelin is an example of a gonadotrophin-releasing hormone
(GnRH) agonist
Degenerative cervical myelopathy
Degenerative cervical myelopathy (DCM) has a number of risk
factors, which include smoking due to its effects on the
intervertebral discs, genetics and occupation - those exposing
patients to high axial loading [1].
The presentation of DCM is very variable. Early symptoms are
often subtle and can vary in severity day to day, making the
disease difficult to detect initially. However as a progressive
condition, worsening, deteriorating or new symptoms should be a
warning sign.
DCM symptoms can include any combination of [1]:
 Pain (affecting the neck, upper or lower limbs)
 Loss of motor function (loss of digital dexterity,
preventing simple tasks such as holding a fork or doing
up their shirt buttons, arm or leg weakness/stiffness
leading to impaired gait and imbalance
 Loss of sensory function causing numbness
 Loss of autonomic function (urinary or faecal
incontinence and/or impotence) - these can occur and do
not necessarily suggest cauda equina syndrome in the
absence of other hallmarks of that condition
 Hoffman's sign: is a reflex test to assess for cervical
myelopathy. It is performed by gently flicking one finger
on a patient's hand. A positive test results in reflex
twitching of the other fingers on the same hand in
response to the flick.
The most common symptoms at presentation of DCM are
unknown, but in one series 50% of patients were initially
incorrectly diagnosed and sometimes treated for carpal tunnel
syndrome [2].
An MRI of the cervical spine is the gold standard test where
cervical myelopathy is suspected. It may reveal disc degeneration
and ligament hypertrophy, with accompanying cord signal
change.
All patients with degenerative cervical myelopathy should be
urgently referred for assessment by specialist spinal services
(neurosurgery or orthopaedic spinal surgery). This is due to the
importance of early treatment. The timing of surgery is important,
as any existing spinal cord damage can be permanent. Early
treatment (within 6 months of diagnosis) offers the best chance of
a full recovery but at present, most patients are presenting too late.
In one study, patients averaged over 5 appointments before
diagnosis, representing >2 years.
Currently, decompressive surgery is the only effective treatment.
It has been shown to prevent disease progression. Close
observation is an option for mild stable disease, but anything
progressive or more severe requires surgery to prevent further
deterioration. Physiotherapy should only be initiated by specialist
services, as manipulation can cause more spinal cord damage.
References
1. Baron EM, Young WF. Cervical spondylotic myelopathy: a
brief review of its pathophysiology, clinical course, and diagnosis.
Neurosurgery. 2007 Jan;60(1 Supp1 1):S35-41.
2. Behrbalk E, Salame K, Regev GJ, Keynan O, Boszczyk B,
Lidar Z. Delayed diagnosis of cervical spondylotic myelopathy by
primary care physicians. Neurosurg Focus. 2013 Jul;35(1):E1.
DVLA: neurological disorders
The guidelines below relate to car/motorcycle use unless
specifically stated. For obvious reasons, the rules relating to
drivers of heavy goods vehicles tend to be much stricter
Epilepsy/seizures - all patient must not drive and must inform the
DVLA
 first unprovoked/isolated seizure: 6 months off if there
are no relevant structural abnormalities on brain imaging
and no definite epileptiform activity on EEG. If these
conditions are not met then this is increased to 12 months
 for patients with established epilepsy or those with
multiple unprovoked seizures:
o may qualify for a driving licence if they have
been free from any seizure for 12 months
o if there have been no seizures for 5 years (with
medication if necessary) a ’til 70 licence is
usually restored
 withdrawawl of epilepsy medication: should not drive
whilst anti-epilepsy medication is being withdrawn and
for 6 months after the last dose
Syncope
 simple faint: no restriction
 single episode, explained and treated: 4 weeks off
 single episode, unexplained: 6 months off
 two or more episodes: 12 months off
Other conditions
 stroke or TIA: 1 month off driving, may not need to
inform DVLA if no residual neurological deficit
 multiple TIAs over short period of times: 3 months off
driving and inform DVLA
 craniotomy e.g. For meningioma: 1 year off driving*
 pituitary tumour: craniotomy: 6 months; trans-sphenoidal
surgery 'can drive when there is no debarring residual
impairment likely to affect safe driving'
 narcolepsy/cataplexy: cease driving on diagnosis, can
restart once 'satisfactory control of symptoms'
 chronic neurological disorders e.g. multiple sclerosis,
motor neuron disease: DVLA should be informed,
complete PK1 form (application for driving licence
holders state of health)
*if the tumour is a benign meningioma and there is no seizure
history, licence can be reconsidered 6 months after surgery if
remains seizure free
Neuropathic pain
Neuropathic pain may be defined as pain which arises following
damage or disruption of the nervous system. It is often difficult to
treat and responds poorly to standard analgesia.
Examples include:
 diabetic neuropathy
 post-herpetic neuralgia
 trigeminal neuralgia
 prolapsed intervertebral disc
NICE updated their guidance on the management of neuropathic
pain in 2013:
 first-line treatment*: amitriptyline, duloxetine,
gabapentin or pregabalin
o if the first-line drug treatment does not work try
one of the other 3 drugs
o in contrast to standard analgesics, drugs for
neuropathic pain are typically used as
monotherapy, i.e. if not working then drugs
should be switched, not added
 tramadol may be used as 'rescue therapy' for
exacerbations of neuropathic pain
 topical capsaicin may be used for localised neuropathic
pain (e.g. post-herpetic neuralgia)
 pain management clinics may be useful in patients with
resistant problems
*please note that for some specific conditions the guidance may
vary. For example carbamazepine is used first-line for trigeminal
neuralgia
 Site of compression Features
The NICE guidelines advise that when a first-line medication is
not effective then that medication should be stopped and another Reduced knee reflex
first-line medication should be tried. Neuropathic medications Positive femoral stretch test
should be given as monotherapy outside of specialist pain clinics. Sensory loss dorsum of foot
When prescribing amitriptyline it should be trialled for a period of L5 nerve root Weakness in foot and big toe dorsiflexion
6-8 weeks with at least 2 weeks at the maximum dose starting an compression Reflexes intact
antimuscarinic agent risks precipitating an exacerbation of Positive sciatic nerve stretch test
symptoms from glaucoma.
Sensory loss posterolateral aspect of leg
and lateral aspect of foot
First-line treatment of neuropathic pain is a choice of S1 nerve root
Weakness in plantar flexion of foot
amitriptyline, duloxetine, gabapentin, or pregabalin. compression
Reduced ankle reflex
Positive sciatic nerve stretch test

Rheumatoid arthritis: ocular manifestations Management

Ocular manifestations of rheumatoid arthritis are common, with
25% of patients having eye problems

Ocular manifestations  similar to that of other musculoskeletal lower back pain:

analgesia, physiotherapy, exercises
o NICE recommend using the same drugs as for
back pain without sciatica symptoms i.e. first-
 keratoconjunctivitis sicca (most common) line is NSAIDs +/- proton pump inhibitors
 episcleritis (erythema) rather than using neuropathic analgesia (e.g.
 scleritis (erythema and pain) duloxetine)
 corneal ulceration  if symptoms persist e.g. after 4-6 weeks) then referral for
 keratitis consideration of MRI is appropriate

Iatrogenic Pseudogout
Pseudogout is a form of microcrystal synovitis caused by
the deposition of calcium pyrophosphate dihydrate crystals in the
 steroid-induced cataracts synovium. For this reason, it is now more correctly termed acute
 chloroquine retinopathy calcium pyrophosphate crystal deposition disease.

Pseudogout is strongly associated with increasing age. Patients

Lower back pain: prolapsed disc who develop pseudogout at a younger age (e.g. < 60 years)
A prolapsed lumbar disc usually produces clear dermatomal leg usually have some underlying risk factor, such as:
pain associated with neurological deficits.

Features
 haemochromatosis
 hyperparathyroidism
 low magnesium, low phosphate
 leg pain usually worse than back
 acromegaly, Wilson's disease
 pain often worse when sitting

Features
The table below demonstrates the expected features according to
the level of compression:
 knee, wrist and shoulders most commonly affected
 joint aspiration: weakly-positively birefringent
Site of compression Features rhomboid-shaped crystals
Sensory loss over anterior thigh  x-ray: chondrocalcinosis
Weak hip flexion, knee extension and hip o in the knee this can be seen as linear
L3 nerve root
adduction calcifications of the meniscus and articular
compression
Reduced knee reflex cartilage
Positive femoral stretch test
Management
Sensory loss anterior aspect of knee and
L4 nerve root
medial malleolus
compression  aspiration of joint fluid, to exclude septic arthritis
Weak knee extension and hip adduction
 NSAIDs or intra-articular, intra-muscular or oral steroids
as for gout